Lipids and Labyrinths: The metabolic maze of mosquito-virus encounters #MetabolismMondays

All the world’s a metabolic dance, early career scientists are leading the way!

Emerging perspectives in metabolism

This week we will meet Dr Cassandra Koh, who is a new faculty at Institut Pasteur. Cassandra is driven by curiosity and is passionate about decoding the molecular choreography between viruses, their insect hosts, and the lipids that entwine them. Her research traces the intricate ways arboviruses hijack mosquito metabolism to fuel their replication and has delved deep into how symbionts like Wolbachia rewire these metabolic pathways. Her brand-new lab will focus on how virus–virus–host interactions offer a nuanced view of disease transmission and microbial co-evolution. But science for Cassandra is more than experiments — it’s a way of asking questions about the world. She credits strong mentors and surprising inspiration from artists and storytellers for shaping her journey. Whether she’s tracing lipid dynamics in mosquito cells or hosting a long lunch for friends, Cassandra believes in curiosity as a compass. She’s currently welcoming collaborators and postdocs interested in exploring the metabolic intersections of immunity, infection, and symbiosis. Check out her work here ! Give her a follow over Bluesky and Twitter.

What was your first introduction to the fields of metabolism and viral infections?

It started with cholesterol. The fruit fly Drosophila melanogaster carries a bacterial endosymbiont called Wolbachia that suppresses pathogenic viral infections in its host. This was a very exciting finding that resulted in a biological intervention strategy against mosquito-transmitted viral diseases based on the stable introduction of the Wolbachia wMelstraininto natural populations of a major mosquito vector species, Aedes aegypti. Eric Caragata had showed that Wolbachia-induced viral suppression became weaker when Drosophila flies had more cholesterol in their diets, leading to the conclusion that Wolbachia and Drosophila viruses were competing for host cholesterol (PMID: 24337107).

Naturally, this led to the question of whether Wolbachia and mosquito-transmitted viruses (also called arboviruses) also compete for host lipid resources. During this study, I learned a lot about the role of lipids in viral infections in mosquitoes from a key paper by Rushika Perera (PMID: 22457619). Her work had shown that dengue virus replication in mosquito cells relies on the activity of fatty acid synthase. In addition, as a flavivirus, dengue virus re-organizes the endoplasmic reticulum membranes to form replication complexes, and this is reflected in an enrichment of lipids that promote membrane curvature and permeability.

You use the term “virus-virus-host” interaction for describing the theme of your lab. Could you share your journey into studying this and using mosquitoes as one of your host model systems? Tell us how you got inspired to further branch out into metabolic aspects of viral infections?

The interaction between arboviruses with their mosquito host is a fascinating subject in itself. Mosquitoes have evolved interesting ways to fight off and tolerate viral infections and the virus seeks to complete its transmission cycle while minimizing virulence to its vector host. With the recent appreciation that mosquitoes harbor a multitude of other viruses that constitutes its resident microbiota, virus-mosquito interaction is no longer a two-player game. These resident viruses are called “mosquito-specific viruses” to distinguish them from the ones that infect and cause disease in humans and animals. They have entered the research spotlight as many studies have reported their ability to reduce or enhance arbovirus infection in mosquitoes, which implies that they have a role to play in disease transmission. Many questions have since sprung up about how they interact with arboviruses and the mosquito host. I am curious to see whether these interactions can be observed in the metabolic dimension.

Your work intersects virology, metabolism, immunology and RNA interference – tell us what studying immune-metabolism means for you. How do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

Immune responses cost energy. Viral infections cost energy. A virus infection is therefore a disruption to immune and lipid homeostasis. There is already some evidence of crosstalk between immune signaling and lipid metabolism modulations in bacteria-infected Drosophila (PMID: 30902902, PMID: 33227003). On top of that, viruses hijack host lipid membranes and reconfigure phospholipids to form viral replication complexes (PMID: 33087565), adding to the toll on the metabolic burden of virus-infected cell. Immune and metabolic regulation therefore go hand in hand and would provide a more holistic view of cellular responses to viral infection.

How has Wolbachia evolved in Drosophila and mosquito species – are a lot of mechanisms of symbiosis evolutionarily conserved? How can studying Wolbachia-insect interactions help us understand symbiont-driven metabolic changes? Could you shed more light on these emerging areas of research.

Wolbachia is a common endosymbiont among arthropods including insects like Drosophila melanogaster and some mosquito species like Aedes albopictus. When it was observed that some Wolbachia strains protect their Drosophila host from viral infection, the notion that the endosymbiont could be introduced into Aedes aegypti mosquitoes, a non-native host, led to the development of Wolbachia-based intervention strategies to limit the spread of viruses transmitted by this major vector species. That Wolbachia is vertically transmitted through the maternal line was a very useful property for a sustainable and self-driving intervention.

Studying how Wolbachia interacts with its hosts would reveal its mechanisms of symbiosis, which would say something about the directions of evolutionary pressures in natural or introduced hosts. These mechanisms might take the shape of metabolic mutualism, immune priming, or something else entirely.

What are the key differences in how Wolbachia and DENV-3 (Dengue virus serotype 3) alter host lipid metabolism?

In our work comparing how Wolbachia and DENV-3 modulate Aedes aegypti lipids, we found that the endosymbiont and the virus individually produce very different lipid alterations. While DENV-3 produced strong elevations, Wolbachia-infected mosquitoes exhibited much milder perturbations of different lipid species, which does not support the Wolbachia-virus competition hypothesis.

Tell us about your findings on association of DENV3 infection with lipid droplet growth and hyperglycemia in mosquitoes? Tell us about your exciting finding of how Cardiolipins are involved in DENV infection.

DENV-3 infection alone strongly elevated levels of triacylglycerols, glycerophospholipids high in polyunsaturated fatty acids, and Amadori-glycated phosphatidylethanolamines in Aedes aegypti mosquitoes. These lipid classes indicate lipid droplet accumulation, cellular membrane remodeling, and viral infection-induced hyperglycemia. The latter is especially interesting as it suggests that this cellular phenomenon, which has previously been observed in human cells infected by dengue viruses, could also occur in mosquito cells.

Cardiolipins were an interesting class of lipids to notice in our dataset because they have not been previously associated with infection. Given its role to maintain mitochondria function, and our finding that cardiolipin depletion disfavors virus replication, we surmised that cardiolipins help to buffer the effects of cellular stresses from viral infection that would otherwise lead to the triggering of the apoptosis regulation pathways.

Building upon your findings in lipid metabolism, what are your upcoming plans? Are there particular metabolic pathways or hormonal regulators you aim to investigate further?

It seems that viruses are strong remodelers of the lipid landscape in mosquitoes. I am keen to see how these modulations take place in different virome backgrounds. The crosstalk between immune and metabolic pathways is something I wish to dive into deeper. It would tell us something about the mechanisms through which host microbiota influence arbovirus infection and transmission.

What role does curiosity play in your life, both within and outside of science? How does studying viral manipulation of host lipid dynamics have implications on evolution of metabolism and its connection to therapies?

Interesting question, because I think I view and approach life in general with curiosity. The fact that I can make a living from finding out stuff is something I am very thankful for.

The insights from host lipids modulation could inform on long-term co-evolutionary dynamics between mosquitoes and their viruses. On the clinical side, understanding what host lipids and metabolites are co-opted by arboviruses, for both the arthropod and vertebrate side of the story, may lead to identification of disease severity risk factors or new therapeutic targets.

Tell us about how you see the future of immune-metabolism evolve with the new upcoming tools – what techniques have you used and which tools are you most excited about?

Single-cell transcriptomics and metabolomics are currently the ‘shiny new things’ in the omics space. As viruses don’t infect every single cell within a tissue, this unprecedented level of resolution would allow us to pinpoint cellular virus-modulated metabolism so much more accurately. I look forward to some paradigm shifting revelations that these techniques will bring about.

What advice would you offer to students and early-career scientists interested in exploring the intersections of metabolism and host-virus interaction? What’s an unexpected place you’ve found inspiration for your work?

Finding the right mentors who showed me what it means to be a scientist has been instrumental in my career path. I have also surprisingly found inspiration from actors and singers, like Hugh Jackman, who (according to a podcast interview I heard) gave himself five years after graduating from drama school to see where his career would take him, or Sabrina Carpenter, who debuted in 2014 and kept going until she produced chart-toppers ten years later.

Science-wise, I think more people should know about this thorough review about virus-vector metabolic interactions (PMID: 37360524).

How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?

Maintaining balance will be always a challenge for me but it helps greatly to know where I draw fulfillment and contentment from. I love my work as a researcher, but personal relationships are what brings me the most joy. I am the grandma friend, so I enjoy hosting long lunches and dinner parties.

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

I think I would have been a food historian. I like learning about how cultures and geography influence the flavor profiles and methods of diverse cuisines. It is the intersection of anthropology and culinary science. I have questions like: Why do cuisines from warmer climates tend to be rich in spices? And what inspired someone to turn spent brewery yeast into a sandwich spread?

Anything else you’d want to highlight?

If immune-metabolism in vector mosquitoes sounds like your kind of vibe, please do get in touch. I would love to hear from postdoc candidates and/or grant co-writers.

Last week we learnt about treating rare metabolic disorders using Drosophila genetics and basic science research via precision medicine, check out the article – Finding Fruit in Flies (Holly Thorpe)

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

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